Ponatinib for Chronic Myeloid Leukemia (CML) Evaluation and Ph+ Acute Lymphoblastic Leukemia (ALL) (PACE)

• ClinicalTrials.gov Identifier: NCT01207440
• Recruitment Status: Completed
• First Posted: September 23, 2010
• Results First Posted: January 29, 2020
• Last Update Posted: February 2, 2021
• Sponsor: Ariad Pharmaceuticals
• Information provided by (Responsible Party): Takeda ( Ariad Pharmaceuticals )

Study Description

Brief Summary:

The purpose of this study is to determine the efficacy of ponatinib in patients with chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast phase (BP) or with philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who either are resistant or intolerant to either dasatinib or nilotinib, or have the (T)hreonine-315-(I)soleucine (T315I) mutation.

Condition or disease	Intervention/treatment	Phase
Chronic Myeloid Leukemia; Ph+ Acute Lymphoblastic Leukemia	Drug: Ponatinib	Phase 2

Detailed Description:

The preliminary analysis of the phase 1 clinical trial revealed evidence of clinical antitumor activity in patients with resistance to approved second-generation tyrosine kinase inhibitors (TKI), dasatinib and nilotinib, including patients with the T315I mutation of the BCR-ABL gene (BCR-ABL). This Phase 1 study, taken together with the strong preclinical data that characterize ponatinib, provides the rationale for moving to a pivotal phase 2 trial of this agent in a population of patients with chronic myeloid leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL) who are resistant or intolerant to prior TKI therapy and in those patients with the T315I mutation.

PACE is a multi-center, international, phase 2, uncontrolled, open-label trial of oral ponatinib in patients with Philadelphia chromosome-positive (Ph+) disease. The study enrolled 449 patients. Participants assigned to 1 of 6 cohorts in accordance with disease group and received:

• Ponatinib 45 mg

This multi-center trial is conducted worldwide. The overall time to participate in this study is 96 months after last dose of study drug treatment.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 449 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients With Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia
• Actual Study Start Date: September 30, 2010
• Actual Primary Completion Date: December 20, 2018
• Actual Study Completion Date: January 17, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort A: CP-CML R-I; CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).	Drug: Ponatinib; Ponatinib tablets.; Other Names: AP24534; Iclusig
Experimental: Cohort B: CP-CML with T315I Mutation; CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).	Drug: Ponatinib; Ponatinib tablets.; Other Names: AP24534; Iclusig
Experimental: Cohort C: Accelerated Phase (AP)-CML R-I; AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).	Drug: Ponatinib; Ponatinib tablets.; Other Names: AP24534; Iclusig
Experimental: Cohort D: AP-CML with T315I Mutation; AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).	Drug: Ponatinib; Ponatinib tablets.; Other Names: AP24534; Iclusig
Experimental: Cohort E: Blast Phase (BP)-CML/Ph+ ALL R-I; BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).	Drug: Ponatinib; Ponatinib tablets.; Other Names: AP24534; Iclusig
Experimental: Cohort F: BP-CML or Ph+ ALL with T315I Mutation; BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).	Drug: Ponatinib; Ponatinib tablets.; Other Names: AP24534; Iclusig
Experimental: Unassigned to Cohorts A-F; Participants who were not assigned to any of the cohorts and have no T315I mutation at study entry and were not R-I to dasatinib or nilotinib, administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).	Drug: Ponatinib; Ponatinib tablets.; Other Names: AP24534; Iclusig

Outcome Measures

Primary Outcome Measures :

1. Percentage of CP-CML Participants With Major Cytogenetic Response (MCyR) [ Time Frame: Up to 12 months after initiation of study treatment ]
   MCyR is defined as percentage of participants with complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Cytogenetic response is the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow (BM). Response is further defined as MCyR: CCyR or PCyR, where CCyR: no Ph+ cells; PCyR: 1 to 35% Ph+ cells.
2. Percentage of AP-CML Participants With Major Hematologic Response (MaHR) [ Time Frame: Up to 6 months after initiation of study treatment ]
   MaHR is defined as percentage of participants with complete hematologic response (CHR) or no evidence of leukemia (NEL). Response criteria for CHR is reported as white blood cells (WBC)≤institutional upper limit of normal, absolute neutrophil count (ANC)≥1000/mm^3, platelets≥100,000/mm^3, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement; Response criteria for NEL is reported as WBC≤institutional upper limit of normal, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm^3≤platelets<100,000/mm^3; (ii) 500/mm^3≤ANC<1000/mm^3.
3. Percentage of BP-CML/Ph+ ALL Participants With MaHR [ Time Frame: Up to 6 months after initiation of study treatment ]
   MaHR is defined as percentage of participants with CHR or NEL. Response criteria for CHR is reported as WBC≤institutional upper limit of normal, ANC≥1000/mm^3, platelets ≥100,000/mm^3, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement; Response criteria for NEL is reported as WBC≤ institutional upper limit of normal, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm^3 ≤platelets<100,000/mm^3; (ii) 500/mm^3≤ANC<1000/mm^3.

Secondary Outcome Measures :

1. Percentage of CP-CML Participants With CHR [ Time Frame: Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose) ]
   Response criteria for CHR is reported as WBC≤institutional upper limit of normal, platelets<450,000/mm^3, no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement (including no hepatomegaly or splenomegaly).
2. Percentage of CP-CML Participants With Confirmed MCyR [ Time Frame: Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose) ]
   Confirmed MCyR is defined as 2 assessments of CCyR or PCyR at least 28 days apart. For CP participants entering the trial in PCyR, confirmed MCyR is defined as 2 assessments of CCyR at least 28 days apart.
3. Percentage of CP-CML Participants With Major Molecular Response (MMR) [ Time Frame: Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose) ]
   MMR is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in transcript).
4. Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MCyR [ Time Frame: Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose) ]
   MCyR is defined as percentage of participants with CCyR or PCyR. Cytogenetic response is the percentage of Ph+ metaphases in BM. Response is further defined as MCyR: CCyR or PCyR, where CCyR: no Ph+ cells; PCyR: 1 to 35% Ph+ cells.
5. Percentage of AP-CML or BP-CML/Ph+ ALL Participants With Confirmed MCyR [ Time Frame: Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose) ]
   Confirmed MCyR is defined as 2 assessments of CCyR or PCyR at least 28 days apart.
6. Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MMR [ Time Frame: Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose) ]
   MMR is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in transcript).
7. Time to Response [ Time Frame: Up to approximately 48 months after first dose ]
   Time to response is defined as the interval from the first dose of study treatment until the criteria for response are first met, censored at the last assessment of response. Median time to response was estimated using the Kaplan-Meier method.
8. Duration of Response [ Time Frame: Up to approximately 48 months after first dose ]
   Duration of Response is defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met, censored at the last date at which the criteria for response are met. Duration of response was estimated by the Kaplan-Meier method as the probability of remaining in response.
9. Progression-free Survival (PFS) [ Time Frame: Every 12 weeks ± 2 weeks from last dose of study drug or the investigator/participant decision to discontinue treatment, whichever occurred later (Up to approximately 96 months after last dose) ]
   PFS is defined as the interval from the first dose of study treatment until the criteria for progression or death are met, censored at the last response assessment. Progression from CP is reported as death, development of AP or BP, loss of CHR (in the absence of cytogenetic response), confirmed by development in complete blood counts (CBCs) at least 4 weeks apart, loss of MCyR, increasing WBC in participant without CHR defined by doubling of WBC to >20K on 2 occasions at least 4 weeks apart; Progression from AP is reported as death, development of confirmed BP, loss of previous major or minor hematologic response over a 2-week period, no decrease from baseline levels in percentage blasts in peripheral blood or BM on all assessments over a 4-week period; Progression from BP or Ph+ ALL is reported as death, increasing blasts in peripheral blood or BM over a 4 week period.
10. Overall Survival (OS) [ Time Frame: From the first dose of study treatment until death (Up to 96 months post last dose) ]
    OS is defined as the interval from the first dose of study treatment until death, censored at the last date at which participant was known to be alive.
11. Number of Participants With Treatment-Emergent Adverse Event (TEAE) and Serious AE (SAE) [ Time Frame: From first dose up to 30 days after last dose of the study drug (Up to approximately 49 months) ]
    An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Participants must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL
• Previously treated with and developed resistance or intolerance to dasatinib or nilotinib OR developed the T3151 mutation after any tyrosine kinase inhibitor (TKI) therapy
• ≥18 years old
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Minimum life expectancy of ≥3 months
• Adequate kidney function
• Adequate liver function
• Normal pancreatic function
• Normal QT Fridericia-corrected interval (QTcF) ≤450 ms for males and ≤470 ms for females
• Negative pregnancy test (if woman of childbearing potential)
• Agree to use effective form of contraception (as applicable)
• Ability to comply with study procedures, in the Investigator's opinion

Exclusion Criteria:

• Received prior TKI treatment within 7 days prior to receiving the first dose of ponatinib, or have not recovered from adverse events (except alopecia) due to agents previously administered.

• Received other therapies as follows:

  1. For CML chronic phase (CP) and accelerated phase (AP) participants, received hydroxyurea or anagrelide within 24 hours prior to receiving the first dose of ponatinib; interferon, cytarabine, or immunotherapy within 14 days prior to first dose of ponatinib; or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the first dose of ponatinib.
  2. For CML blast phase (BP) participants, received chemotherapy within 14 days prior to the first dose of ponatinib.
  3. For Ph+ ALL participants, received corticosteroids within 24 hours before the first dose of ponatinib; or vincristine within 7 days prior to the first dose of ponatinib; or received other chemotherapy within 14 days prior to the first dose of ponatinib.
• Underwent stem cell transplant <60 days prior to receiving first dose of ponatinib
• Evidence of on-going graft versus-host disease (GVHD), or GVHD requiring immunosuppressive therapy
• Taking medications that are known to be associated with Torsades de Pointes
• Require concurrent treatment with immunosuppressive agents (other than corticosteroids prescribed for a short course of therapy)
• Previously treated with ponatinib
• CML CP participants are excluded if they are in Complete cytogenetic response (CCyR)
• Participants with CML AP, CML BP, or Ph+ ALL are excluded if they are in Major Hematologic Response (MaHR).
• Have active Central Nervous System (CNS) disease
• Have significant or active cardiovascular disease
• Have a significant bleeding disorder unrelated to CML or Ph+ALL
• Have a history of pancreatitis or alcohol abuse
• Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL)
• Have malabsorption syndrome or other gastrointestinal illness that could affect absorption of ponatinib
• Diagnosed with another primary malignancy in the past 3 years
• Pregnant or lactating
• Underwent major surgery within 14 days prior to first dose of ponatinib
• Have ongoing or active infection
• Suffer from any other condition or illness that would compromise safety or interfere with evaluation of the drug

Contacts and Locations

Locations

Australia, New South Wales

Royal North Shore Hospital

St Leonards, New South Wales, Australia, 2065

Australia, Queensland

Princess Alexandra Hospital

Woolloongabba, Queensland, Australia, 4102

Australia, South Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia, 5000

Australia, Victoria

Alfred Hospital

Box Hill, Victoria, Australia, 3128

Peter MacCallum Cancer Centre

East Melbourne, Victoria, Australia, 3002

Belgium

UCL Bruxelles

Bruxelles, Belgium, 1200

UZ Leuven

Leuven, Belgium, 3000

France

Institut Bergonie

Bordeaux, France, 33076

Hopital Andre Mignot

Le Chesnay, France, 78157

Hopital Claude Huriez CHRU

Lille, France, 59307

Chu Brabois

Nancy, France, 54551

Hopital Archet

Nice, France, 6202

Hopital St. Louis

Paris, France, 75010

Hopital Edouard Herriot

Pierre-Benite, France, 69495

Entre Hospitalier Universitaire

Poitiers, France, 86021

Hopital de Purpan

Toulouse, France, 31059

Germany

Charite - Universitatsmedizin Berlin,

Berlin, Germany, 13353

Klinikum der Goethe Universitat,

Frankfurt, Germany, 60590

Universitatsklinikum Jena

Jena, Germany, 07747

University of Heidelberg

Mannheim, Germany, 68169

III. Med. Klinik und Poliklinik

Munchen, Germany, 81675

Italy

Universita di Bologna

Bologna, Italy, 40138

University of Modena

Modena, Italy, 41124

University of Milano Bicocca

Monza, Italy, 20052

University of Turin

Orbassano (TO), Italy, 10043

University Tor Vergata

Roma, Italy, 144

Korea, Republic of

The Catholic University of Korea, Seoul St.Mary's Hospital

Seoul, Korea, Republic of, 137-701

Netherlands

VU University Medical Center

Amsterdam, Netherlands, 1081 HV

University Medical Center Groeningen

Groningen, Netherlands, 9713 GZ

Singapore

Singapore General Hospital

Singapore, Singapore, 169608

Spain

Hospital Clinic

Barcelona, Spain, 8036

La Paz

Madrid, Spain, 28046

Hospital Universitario de Salamanca

Salamanca, Spain, 37007

Hospital Clinico of Valencia

Valencia, Spain, 46010

Sweden

Lund University

Lund, Sweden, 22185

Karolinska Hospital

Stockholm, Sweden, 17176

University Hospital Uppsala

Uppsala, Sweden, 75185

United Kingdom

Gartnavel General Hospital

Glasgow, United Kingdom, G12 0XB

Royal Liverpool University Hospital

Liverpool, United Kingdom, L7 8XP

Hammersmith Hospital

London, United Kingdom, W12 0NN

Royal Victoria Infirmary

Newcastle, United Kingdom, NE2 4HH

University of Nottingham

Nottingham, United Kingdom, NG5 1PB

Sponsors and Collaborators

Ariad Pharmaceuticals

Investigators

• Study Director: Medical Director Clinical Science; Takeda

  Study Documents (Full-Text)

Documents provided by Takeda ( Ariad Pharmaceuticals ):

Statistical Analysis Plan  [PDF] December 14, 2010

Study Protocol  [PDF] April 3, 2015

More Information

Publications of Results:

Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Muller MC, Gambacorti-Passerini C, Lustgarten S, Rivera VM, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes TP, Shah NP, Kantarjian HM. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018 Jul 26;132(4):393-404. doi: 10.1182/blood-2016-09-739086. Epub 2018 Mar 22.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Januzzi JL, Garasic JM, Kasner SE, McDonald V, Petrie MC, Seltzer J, Mauro M, Croce K, Berman E, Deininger M, Hochhaus A, Pinilla-Ibarz J, Nicolini F, Kim DW, DeAngelo DJ, Kantarjian H, Xu J, Hall T, Srivastava S, Naranjo D, Cortes J. Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee. J Hematol Oncol. 2022 Jan 6;15(1):1. doi: 10.1186/s13045-021-01221-z. Erratum In: J Hematol Oncol. 2022 Mar 23;15(1):33.

Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio J, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Muller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H; PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013 Nov 7;369(19):1783-96. doi: 10.1056/NEJMoa1306494. Epub 2013 Nov 1.

O'Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer. 2012 Jul 24;12(8):513-26. doi: 10.1038/nrc3317. Erratum In: Nat Rev Cancer. 2012 Dec;12(12):886.

• Responsible Party: Ariad Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01207440
• Other Study ID Numbers: AP24534-10-201; 2010-020414-28 ( EudraCT Number )
• First Posted: September 23, 2010
• Results First Posted: January 29, 2020
• Last Update Posted: February 2, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• URL: https://vivli.org/ourmember/takeda/

Keywords provided by Takeda ( Ariad Pharmaceuticals ):

CML; ALL; PH; ponatinib; Ph+ALL; T315I mutation; Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Myeloproliferative Disorders; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Ponatinib; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents